6Y23

DDR1 kinase autoinhibited by its juxtamembrane region

6Y23 の概要

• エントリーDOI: 10.2210/pdb6y23/pdb
• 分子名称: Epithelial discoidin domain-containing receptor 1, SULFATE ION (3 entities in total)
• 機能のキーワード: kinase, collagen, cell signalling, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 117905.61

構造登録者

Sammon, D.,Hohenester, E.,Leitinger, B. (登録日: 2020-02-14, 公開日: 2020-09-02, 最終更新日: 2024-01-24)

主引用文献

Sammon, D.,Hohenester, E.,Leitinger, B.
Two-step release of kinase autoinhibition in discoidin domain receptor 1.
Proc.Natl.Acad.Sci.USA, 117:22051-22060, 2020

PubMed Abstract: Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase with important functions in organogenesis and tissue homeostasis. Aberrant DDR1 activity contributes to the progression of human diseases, including fibrosis and cancer. How DDR1 activity is regulated is poorly understood. We investigated the function of the long intracellular juxtamembrane (JM) region of human DDR1 and found that the kinase-proximal segment, JM4, is an important regulator of kinase activity. Crystal structure analysis revealed that JM4 forms a hairpin that penetrates the kinase active site, reinforcing autoinhibition by the activation loop. Using in vitro enzymology with soluble kinase constructs, we established that release from autoinhibition occurs in two distinct steps: rapid autophosphorylation of the JM4 tyrosines, Tyr569 and Tyr586, followed by slower autophosphorylation of activation loop tyrosines. Mutation of JM4 tyrosines abolished collagen-induced DDR1 activation in cells. The insights may be used to develop allosteric, DDR1-specific, kinase inhibitors.

PubMed: 32839343
DOI: 10.1073/pnas.2007271117

実験手法

X-RAY DIFFRACTION (2.58 Å)